Review of: Anton RF et al, JAMA 2006;295(17):2003–2017

Conducted from 2001 to 2004 and published in 2006, the COMBINE study was the largest pharmacotherapy study that assessed the treatment of alcohol use disorder (AUD). Although there were significant data on the use of naltrexone and acamprosate (both had been FDA approved), widespread use had not been adopted, and extended release naltrexone was still undergoing its approval process. The prior large NIAAA-funded study of AUD interventions was Project MATCH, which focused exclusively on psychosocial therapies, whereas COMBINE evaluated the effectiveness of naltrexone, acamprosate, and specialty therapy both alone and in combination. By doing so, the authors hoped to shed light on the following questions: 1) Are there synergistic intervention combinations? 2) Is effective treatment of AUD feasible in a primary care setting?

1383 recently abstinent subjects across 11 academic sites were randomly assigned to 9 groups, and the trial was conducted over 16 weeks. Outcomes included percent days abstinent and return to heavy drinking. Combined behavioral intervention (CBI), an amalgamation of the evidence-based therapies used in Project MATCH (cognitive behavioral therapy, 12-step facilitation, and motivational interviewing), is a specialty therapy developed for this study. One group received only CBI (no pills) and the 8 pill-taking groups received varying combinations of CBI, acamprosate, naltrexone, and placebo, including a placebo-only group. Those eight groups also received medical management (MM), a brief evaluative and supportive intervention with a health care professional similar to a primary care encounter.

Compared to placebo, naltrexone reduced the percentage of participants who returned to heavy drinking (68.2% vs 71.4%; p = 0.02), but not percent days abstinent (78.8% vs 77.2%; p = 0.25). In contrast, acamprosate did not separate from placebo in any condition or interaction. A more striking result, however, was how poorly the CBI-only group performed in comparison to the pill-taking + MM groups, including in comparison to the placebo groups. For instance, placebo groups produced significantly greater percent days abstinent than CBI alone (p < 0.001). Although the authors point out a statistically significant interaction between CBI and naltrexone, this was not very convincing, as the data for this interaction included subjects receiving placebo. For those who received actual naltrexone, the CBI + naltrexone group was no better than naltrexone alone.

CATR’s Take
This study demonstrates that evidence-based AUD treatment can be delivered in non-specialty settings, which would expand access tremendously. Although clearly not a panacea, naltrexone performed well in the MM model. Acamprosate did not fare well, and it may perform better when initiated after a longer period of abstinence. This was also a disappointing study for psychotherapy, but the findings aren’t enough reason to write it off, and the role of psychosocial interventions in addiction treatment was discussed in the prior issue of CATR.